M.H.P. van Lieshout
- Cell-specific pattern recognition receptor signaling in antibacterial defense
T. van der Poll
C. van 't Veer
A.F. de Vos
- Award date
- 24 September 2015
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Sepsis, the syndrome that describes infection complicated by acute organ failure, is most frequently caused by bacterial pneumonia and infection originating from the abdominal cavity and is a major cause of morbidity and mortality globally. A brisk and firm initial host response is needed for clearance of the pathogen, but on the other hand can induce tissue and organ injury.
In this thesis we describe the differential contribution of Toll-like receptors (TLRs) and their intracellular adapter proteins in different cell-types to host defense and organ injury during the course of pneumonia. We used genetically modified mice in experimental sepsis models with the gram-negative pathogens Klebsiella pneumoniae and Pseudomonas aeruginosa.
Moreover, we focused on the role of another innate detection system called the "NLRP3-inflammasome" during pneumonia caused by Streptococcus (S.) pneumoniae. We observed that this protein complex conferred protection in a model using one specific pneumococcal strain but played a detrimental role during infection with a virulent, S. pneumoniae strain. These data demonstrate that the contribution of proximal innate detection systems can vary between strains even within the same bacterial species.
Finally, we examined the effect of anti-TLR4 therapy, designed to modulate excessive inflammation in human sepsis, in a model of murine abdominal sepsis and found that therapeutic targeting of TLR4 signaling can potentially interfere with bacterial clearance even in the context of antibiotic therapy, but on the other hand can help limit some aspects of tissue injury depending on the infectious dose and kinetics of the infection model.
- Research conducted at: Universiteit van Amsterdam